Epidermal morphogenesis underlies much of animal development, yet the molecular mechanisms of epithelial movements are still poorly understood. We study the epidermis of the nematode Caenorhabditis elegans as a simple model for many aspects of epithelial morphogenesis. Our long-term goal is to identify the proteins that regulate epidermal morphogenesis. We have identified genes that function in neuronal cell signaling to regulate C. elegans epidermal morphogenesis. These include an Eph receptor tyrosine kinase (VAB-1), an ephrin ligand 3. Our genetic analysis showed that Eph signaling forms part of a network of partly redundant for the VAB-1 receptor (EFN-l/VAB-2), and the LAR-type receptor tyrosine phosphatase PTP- signaling pathways that regulate C. elegans morphogenesis. We will analyze how Eph signaling functions to regulate cell behaviors in morphogenesis, both to better understand the mechanisms of Eph signaling pathways and to elucidate their in vivo function in morphogenesis. We have three specific aims. (1) We will characterize a divergent C. elegans ephrin, EFN-4. Mutations in EFN-4 affect morphogenesis. We will test whether EFN-4 is a ligand with the VAB-1 receptor and whether it modulates effects of other C. elegans ephrins. We will also search for novel EFN-4 binding proteins. (2) Our earlier work showed that Eph signaling function is partly redundant with two other pathways. In screens to identify new components of such pathways, we have identified a locus that shows synthetic-lethal interactions with vab-1. To better understand the pathways that interact with Eph signaling we will characterize this gene and identify other vab-1-interacting genes. (3) Suppressor analysis can identify components of signaling pathways that may not be found by direct genetic screens. We have identified suppressors of vab-1 loss-of-function mutations and will analyze one of these suppressors genetically and by molecular cloning. We will also generate gain-of-function (constitutively activated) versions of VAB-1 and use these in new suppressor screens. Eph signaling plays many roles in neural and vascular development and has been implicated in tumorigenesis. These aims take advantage of genetic approaches available in C. elegans to study Eph signaling and its roles in neural and epidermal morphogenesis.